CN105163663A - Monitor and system for monitoring living organisms - Google Patents
Monitor and system for monitoring living organisms Download PDFInfo
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- CN105163663A CN105163663A CN201480024971.8A CN201480024971A CN105163663A CN 105163663 A CN105163663 A CN 105163663A CN 201480024971 A CN201480024971 A CN 201480024971A CN 105163663 A CN105163663 A CN 105163663A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
- A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
- A61B5/7271—Specific aspects of physiological measurement analysis
- A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/65—Raman scattering
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2505/00—Evaluating, monitoring or diagnosing in the context of a particular type of medical care
- A61B2505/05—Surgical care
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/02—Details of sensors specially adapted for in-vivo measurements
- A61B2562/0233—Special features of optical sensors or probes classified in A61B5/00
- A61B2562/0238—Optical sensor arrangements for performing transmission measurements on body tissue
Abstract
Provided is a monitor (10) for monitoring the condition of the interior of a living organism from the surface of the living organism. The monitor (10) is provided with: a probe (23) which includes an observation window (21) and is attached to the organism surface (2); a unit (25) which irradiates, with a laser, at least a portion of an observation region (3) on the organism surface (2) accessed via the observation window (21); a unit (27) which detects scattered light (28) resulting from the laser irradiation from each of a plurality of observation spots distributed two-dimensionally throughout the observation region (3); a Doppler analysis unit (51) and a SORS analysis unit (52) which, on the basis of the scattered light (28) obtained from the plurality of observation spots, narrow down the plurality of observation spots to a first observation spot for which it is determined that scattered light including information on a target section of the organism interior can be obtained; and a CARS analysis unit (53) which obtains the optical spectrum for at least one component from the first observation spot or observation spots surrounding the same, and outputs first information indicating the condition of the organism interior on the basis of the intensity of the spectrum.
Description
Technical field
The present invention relates to a kind of monitor that the internal state of organism is monitored and the system that biological active substances is provided according to the information from monitor.
Background technology
The diagnostic kit that necessity, blood that the invasive in the glycoregulatory mensuration of Fructus Vitis viniferae can be avoided to test carry the use of mark is disclosed in Japanese Unexamined Patent Publication 2007-192831 publication.This diagnostic kit is the richness comprising ormal weight
13c glucose and expiration extraction vessel, the glycemic control mensuration diagnostic kit of examinee, in one embodiment, this diagnostic kit also comprises multiple expiration extraction vessel, in addition, in other embodiments, this diagnostic kit is used for the diagnosis of diabetes, in addition, in other embodiments, this diagnostic kit is also for the diagnosis of insulin resistance.
Summary of the invention
Breath analysis right and wrong are invasive, but are difficult to monitor the state of organism continuously.
A mode of the present invention is a kind of monitor, from organism surface in the face of the state of organism inside monitors.Monitor has: probe, and it comprises the observation window being installed in organism surface; Illumination unit, the irradiating laser at least partially of its viewing area to the organism surface of accessing via observation window; Detecting unit, its each observation station from the multiple observation stations formed intermittently in the mode being scattered in viewing area two-dimensionally or formed continuously in the mode scanned viewing area detects the scattered light produced because laser irradiates; From multiple observation station, the unit of the first observation station being judged as the scattered light of the information that can obtain the target part comprising organism inside is limited according to the scattered light obtained from multiple observation station; And obtain the spectrophotometric spectra of at least one composition from the first observation station or the observation station around it and export the unit of the first information of the state representing organism inside according to the intensity of this spectrophotometric spectra.
Preferably, monitor also has updating block, this updating block the first observation station or obtain around it different multiple parts of the degree of depth from organism surface, the spectrophotometric spectra of the first composition, and limit further according to the intensity of the spectrophotometric spectra of the first composition or upgrade the first observation station.
One of alternate manner of the present invention is a kind of control method of system, and this system has from organism surface in the face of the state of organism inside carries out the monitor that monitors.Monitor has: probe, and it sets multiple observation stations of disperseing two-dimensionally with the first interval at organism surface; The unit exporting scattered light from each observation station of multiple observation station is made to organism surface surface irradiation laser; And the unit detected from the scattered light of multiple observation station, this control method comprises the following steps.
1. obtain scattered light from each observation station of multiple observation station, from multiple observation station, obtain first observation station relevant to veins beneath the skin according to laser doppler.
2. the first observation station or obtain around it different multiple parts of the degree of depth from organism surface, the spectrophotometric spectra of the first composition, and judge the target part under organism surface according to the intensity of the spectrophotometric spectra of the first composition.
3. the first information of the internal state representing organism is exported according to the intensity of the spectrophotometric spectra of at least one composition of target part.
Preferably, this control method is further comprising the steps of.
4. the first observation station or obtain around it different multiple parts of the degree of depth from organism surface, the spectrophotometric spectra of the first composition, and limit further according to the intensity of the spectrophotometric spectra of the first composition or upgrade the first observation station.
The spectral analysis technique such as near infrared spectroscopy, Raman spectroscopy can be used to carry out compound, the subcutaneous tissue existed in the body fluid such as analyzing blood, and the biochemical material, cell component etc. in analysing body fluid can be carried out according to its analysis result.Therefore, Biont information should be able to be obtained by spectrum analysis.But in each several part of organism, the concentration of biochemical material, cell component are different.Therefore, accessed packets of information, containing the information of the various structures under organism surface, causes the information being set to target to be buried in out of Memory, noise, thus is difficult to the state estimating organism.
In above-mentioned monitor and control method, be set with multiple observation station at the viewing area of the organism surface can accessed via the observation window of popping one's head in.Further, and whole data of the multiple observation station of non-usage, but obtain spectrophotometric spectra by the part that the unit carrying out limiting locks onto multiple observation station, and export the first information of the internal information representing organism according to these data.Thus, the information relevant to the limited part under organism surface optionally can be obtained, therefore, it is possible to suppress the information being set to target to be buried in the situation of out of Memory, noise.
Accompanying drawing explanation
Fig. 1 represents health management system arranged block diagram.
Fig. 2 is the block diagram representing monitor.
Fig. 3 is the figure representing viewing area and observation station.
Fig. 4 is the figure representing Raman spectrum.
Fig. 5 is the block diagram of presentation of events identification module.
Fig. 6 is the figure of the change representing glucose.
Fig. 7 is the flow chart representing health management system arranged action.
Detailed description of the invention
Below, be described using following situation: subcutaneous blood capillary is assigned to obtain its spectrophotometric spectra as target portion, obtain thus comprise flow in blood vessel composition, such as glucose the information of amount.
In monitor of the present invention, be set with multiple observation station at the viewing area of the organism surface can accessed via the observation window of popping one's head in.The unit carrying out limiting is first according to the scattered light obtained from multiple observation station, and the observation station that can obtain the information of the target part of organism inside limits or is locked as the first observation station.If target part is the blood capillary of organism inside, then pay close attention to the spectrum of the laser doppler comprised in scattered light, can by determining whether that this observation station is locked as the first observation station by the observation station can observing blood flow.Target part is not limited to blood capillary, such as, if lymph gland, then focus on the spectrum of the composition detected with maximum intensity when spectrum analysis carried out to the composition comprised in lymph gland, can by determining whether that this observation station is locked as the first observation station by the observation station can observing this composition.
The unit carrying out limiting, when locking the first observation station, not only can be obtained the profile of two dimension, also can obtain the profile of the three-dimensional of the profile comprising depth direction.If blood capillary, then can, based on the flow components comprised in laser doppler, mathematical model be used to obtain the profile of depth direction.If mensuration Raman spectrum, then can usage space skew Raman spectroscopy (SORS:SpatiallyOffsetRamanSpectroscopy).
Assuming that first observation station of blood flow of observation blood capillary be positioned at the top of blood capillary or its near.The unit exported as the first information of Biont information locks onto the first observation station or the observation station around it, obtains the spectrophotometric spectra of at least one composition, exports the first information of the state representing organism inside according to the intensity of this spectrophotometric spectra.
It is effective for arranging in this monitor with lower unit: this unit the first observation station or obtain around it different multiple parts of the degree of depth from organism surface, the spectrophotometric spectra of the first composition, and limit further according to the intensity of the spectrophotometric spectra of the first composition or upgrade the first observation station.Obtained the spectrum of the different multiple parts of the degree of depth from organism surface by spectrographic method, can judge that whether this spectrum be the spectrum of target part according to the intensity of the first composition comprised in spectrum.Such as, when wanting the concentration detecting the biochemical material existed in blood vessel, if people, then comprise the skin (epidermis), corium, the subcutaneous tissue that form surface near organism surface, blood vessel is present in corium or subcutaneous tissue mostly.But the distance from surface to blood vessel is different according to position difference, and, different according to patient's difference, sometimes also different according to posture difference at that time.
In this monitor, by the spectrum that the intensity of judging to exist in blood maximum compositions in the spectrum that the degree of depth is different is the strongest, the spectrum of blood can be judged as.Then, by judging the intensity of the one or more compositions comprised in the spectrum of blood, the first information represented based on the internal state of the organism of the concentration in blood can be exported.Target part is not limited to blood vessel, also can be subcutaneous fat, lymph node, also can generate the first information of the state representing organism inside according to the composition of the different multiple target part of the degree of depth.The value of the representational clinical biochemical Epidemiological Analysis obtained from the spectrum blood is glycolated hemoglobin, AST, ALT, triglyceride, G-GTP, LDH, ALP, the adiponectins etc. such as cholesterol, blood glucose value (glucose), HbA1c.
Easily one of spectroscopic analysis methods carrying out degree of depth adjustment is confocal Raman analysis.By using one or more confocal Raman analysis unit, also can obtain and being present in the composition of target part or the three-dimensional information of cell.The incident illumination of spectrum analysis can be the light that LED or other wavelength region are wider, but the laser that optimal wavelength region is narrow.When the tunable laser that can carry out wavelength convert is used as light source, easily carry out degree of depth adjustment, and the higher spectrum of the precision of target part can be obtained by resonance Raman spectroscopy.
Another spectroscopic analysis methods that can generate the profile of depth direction is spatial deviation Raman spectroscopy (SORS).And, as the method that can generate the profile of depth direction accurately, the CARS spectrum after the present inventor's irradiating angle advocated by controlling pump light or the stokes light used in coherent anti-Stokes Raman spectroscopy (CARS:CoherentAnti-stokesRamanSpectroscopy (scattering: scattering)) obtains spatial deviation.
About multiple observation station, can by multiple observation station optionally irradiating laser set, also optionally can obtain scattered light from each observation station of multiple observation station.Thus, probe can comprise laser is guided to the output unit of each observation station of multiple observation station from the Unit selection carrying out irradiating.Probe can also comprise input block scattered light being guided to detecting unit from each observation station of multiple observation station.One example of output unit and input block comprises the reflecting mirror of MEMS or micromachine or the aggregation (MD, Micro-mirrorDevice: micro mirror element) of reflecting mirror.In viewing area, one or more laser spots can be formed intermittently or continuously, thus multiple observation station can be formed.
Another example of output unit and input block is photonic crystal fiber (PCF:Photoniccrystalfiber), microstructured optical fibers (Micro-structuredFiber), porous optical fiber (Holeyfiber), fibre bundle etc. form the optical component of multiple focus and comprise the chopper matrix (Japanese: シ ャ ッ タ ー マ ト リ Network ス) of MEMS or micromachine or the combination of MD.One or more point can be formed intermittently in viewing area, thus a large amount of observation stations can be formed.
Preferably, multiple observation station can be set in viewing area with the interval of 1 μm ~ 1000 μm by output unit and input block.It is further preferred that multiple observation station is set in viewing area with the interval of 10 μm ~ 100 μm.Preferably, hypodermic mean size is several μm to tens μm, and monitor possesses the resolution of below hundreds of μm or hundreds of μm.
Preferably probe is close to skin.Probe can be installed on skin via fluids such as gels, but, when considering the convenience of user and installing sense, preferably observation window is close to organism surface via diffusibility multiple aperture plasma membrane.The thin film that one example of diffusibility multiple aperture plasma membrane is PDMS (polydimethylsiloxane), hybrid silica (Japanese: Ha イ Block リ ッ De シ リ カ) is made.
By by this monitor and the dispensing unit combination providing biological active substances according to the first information obtained from monitor to organism, can provide a kind of for medicine system.This system is used for the treatment, health management, rehabilitation etc. of patient.No matter biological active substances is organism material or synthetic, all represents the material monomer to biological performance physiological action or pharmacological action or chemicals group.Biological active substances comprises vitamin, mineral, ferment, hormone etc., and an example of hormone is insulin.
Preferably this system also has the action monitor unit of the external status obtaining or predict organism.Preferably this system also has except controlling the amount of biological active substances that provides to organism from dispensing unit or the unit of kind according to except the first information, also according to the information (the second information) from action monitor unit.The situation in the organism of patient's following a period of time is predicted according to the rhythm of life of patient, action model, or predict the change of the situation from now in organism according to having a meal practically, moving, type, the amount of thrown in biological active substances can be controlled thus for the present situation of organism in advance.Therefore, it is possible to control type and the amount of biological active substances, make to form the situation of patient and the state of mating of taking action.
Further, preferably this system also has the unit first information and the running-active status of dispensing unit being outputted to outside.Doctor, nurse etc. can carry out telemonitoring by this system to patient.
The control method comprising the system of above-mentioned monitor illustrated in this description can be recorded in suitable recording medium as program or program product, or can provide this control method via the Internet.In addition, also the control method of this system can be provided as comprising the method carrying out monitoring from organism surface in the face of the state of organism inside by spectrographic method.Both the method for the method as treatment patient can be provided, also the method for the method as the health of leading subscriber can be provided, can also using the method as being used for preventing from the method for seizure of disease in advance to provide.
Preferably, when system have provide the dispensing unit of biological active substances to organism, control method comprises following selection step: according to the first information select by dispensing unit provide and deliver biological active substances and amount.
Preferably, when system has the action monitor unit of the external status obtaining or predict organism, step is selected to comprise the following steps: except selecting by the amount of the biological active substances of dispensing unit dispensing or kind according to the information of external status according to except the first information, also.
In FIG, the Sketch of healthy life (healthvital) parametric controller (controlling or adjustment system) of Noninvasive is shown by block diagram.This system 1 comprises sensor platform 10, analytical engine 120, drug delivery unit 130 and event tracking unit 140.In addition, below, make to maintain the life of diabetics for the health of managing patient and make patient health and the system 1 of enthusiastically living is described, but the disease can carrying out tackling for platform with this system 1 is not limited to diabetes.
Sensor platform (monitor) 10 can for the amount of the glucose in diabetics non-invasively continuous monitoring blood.One example of sensor platform 10 is FTIR-Raman spectrum analysis unit of Wavelength variable type.The sensor being equipped on sensor platform 10 is not necessarily a kind of, also can be multiple, also can possess the sensor of multiple identical type.Such as, also the sensor of arbitrary type in infrared spectrum analysis device, near infrared spectrum analysis device, quality analysis apparatus, ion mobility etc. or the sensor of multiple type organism surface can be installed on jointly, also organism surface can be installed on dispersedly.
Sensor included by monitor 10 not easily hinders life or the degree of activity and lightweight when being miniaturized being installed on human body or organism by technology such as MEMS, further, require that the power consumption of this sensor is low to utilize lightweight battery to work long hours.Power supply can be compact battery, and also can be the battery that solaode etc. is generated electricity by outside energy, the battery generated electricity by the activity of body temperature, the reaction of other organism and organism, can also be by the battery of these battery combination.
Require that monitor 10 precision is high and possess zero offset capability.Zero offset capability comprises following functions: the mensuration target part automatically finding organism inside from the surface of organism, with independently automatic tracing or the information that rediscovers from this target part such as activity of organism.
Expect that the information (Biont information) 150 measured by the monitor 10 pairs of diabeticss is concentration of glucose in blood, glycolated hemoglobin concentration (HbA1c concentration), glycosylated albumin concentration, blood pressure, blood oxygen saturation, cancer markers and other maintain relevant key element to health and lives.
In fig. 2, Raman spectrum analysis unit 11 is illustrated as one of monitor 10.This unit 11 comprises optics machine 20, tunable laser instrument 30, detector 40 and signal processor 50, all by chip, these chips can be installed on the surface (skin) 2 of organism (human body) 7 with stacked state.
Optics machine 20 is MEMS optical chips, has: the probe 23 comprising the observation window 21 being installed in skin 2; Unit 25, it is to the irradiating laser at least partially of the viewing area 3 of the skin 2 of accessing via observation window 21; And unit 27, its each observation station from the multiple observation stations formed intermittently in the mode being scattered in viewing area 3 two-dimensionally or formed continuously in the mode scanned viewing area detects the scattered light produced because laser irradiates.
Laser beam irradiation unit (optical system) 25 is corresponding with CARS, comprise the first light path 25a and the second light path 25b, this first light path 25a guides the stokes light 31 that the angular frequency obtained from tunable laser instrument 30 is ω s, and this second light path 25b diagonal frequencies is that the pump light 32 of ω p guides.First light path 25a and the second light path 25b comprises Polarizer P, half-wave plate HWP, 1/4 wavelength plate QWP etc.Laser beam irradiation unit 25 is synthesized stokes light 31 and pump light 32 by dichroic beam combiner BC, and via probe 23 to viewing area 3 irradiating laser.
Laser machine 30 is chip-shaped laser chip or the LED unit of the laser exporting multiple wavelength.As Wavelength variable laser machine, Littrow (Littrow) type laser machine, Li Teman (Littmann) type laser machine etc. can be used.Especially, preferred laser machine 30 can supply wavelength variable stokes light 31 and wavelength variable pump light 32.One example of the wave-length coverage of stokes light 31 is 1000nm ~ 1100nm, more preferably 900nm ~ 1450nm.One example of the wave-length coverage of pump light 32 is 700nm ~ 800nm.Laser machine 30 also can generate the laser of these wave-length coverages by the combination of multiple light source cell.
Detecting unit (secondary optical system) 27 comprises: light beam dividing plate BS, and the angular frequency supplied from probe 23 is the anti-Stokes light isolation of ω as by it; And light path 27a, the scattered light (secondary light) 28 obtained from the multiple observation stations formed in the mode being scattered in viewing area 3 is two-dimensionally supplied to photodetector 40 by it.Detecting unit 27 also can comprise lens L, laser blocking filter, diffraction grating etc. for making scattered light 28 converge at detector 40.Detecting unit 27 also can comprise flip mirror (flipmirror), to be split by scattered light 28 and to be supplied to dissimilar detector, such as CCD and photodiode.
Photodetector 40 can be the sensor being configured with detecting element as CCD or CMOS two-dimensionally.Photodetector 40 also can be photodiode, applicable is fast response time, low noise and the InGaAs photodiode of frequency characteristic excellence.Especially, when probe 23 possesses the high-resolution selection function of observation station, do not need the selection function with observation station in photodetector 40 side, or there is the selection function of low resolution.Thus, photodiode can be applied as detector 40, thus can the signal of output low noise.
Probe 23 comprises output unit 23a and input block 23b, and the viewing area 3 that this output unit 23a can access via observation window 23 forms multiple observation station, and this input block 23b can optionally obtain scattered light 28 from multiple observation station.MD unit and the combination of many optical fiber, by integrated for the polygonal mirror of MEMS type and the MD unit that obtains is used as output unit 23a, be used as input block 23b, can select acquisition scattered light 28 under the state not having crosstalk from multiple observation station by this probe 23.
The situation being set with multiple observation station 5 at viewing area 3 has been shown in Fig. 3.In this embodiment, in the viewing area 3 of 600 μm × 600 μm, with 50 μm for spacing setting has 12 × 12 observation stations 5.The size of viewing area 3, the spacing of observation station 5, quantity are examples, are not limited thereto.Also can not, with fixing spacing setting observation station 5, MD unit also can be used to set observation station 5 continuously.Require that the repeatability of the position of each observation station 5 is high.In addition, about the spacing of observation station 5, expect the size of the blood capillary 8 that can detect fully as detected object, such as diameter is several μm ~ tens μm, and can select and obtain the information of blood capillary 8.Thus, the spacing of observation station 5 is preferably 1 μm ~ about 1000 μm, is more preferably 10 μm ~ about 100 μm.
Optics machine 20 also can possess the function as the confocal Raman microscope of 3D.
The signal processor 50 of control both optical machine 20 comprises laser-Doppler resolution unit 51, SORS resolution unit 52, CARS resolution unit 53,3D profile unit (3D contourograph) 54, memorizer 55 and Biont information generation unit 56.Doppler's resolution unit 51 and SORS resolution unit 52 play function as with lower unit: this unit, according to the scattered light 28 obtained from multiple observation station 5, limits the first observation station 5a being judged as the scattered light 28 of the information of the blood capillary 8 as target part that can obtain the inside comprising organism 7 from multiple observation station 5.
3D contourograph 54 locks the first observation station 5a covering blood capillary 8 two-dimensionally, for the profile in these the first observation station 5a Formation Depth directions according to the output of laser-Doppler resolution unit 51 and SORS resolution unit 52.Form the three-D profile 57 of the blood capillary 8 about viewing area 3 thus, and be stored in memorizer 55.The three-D profile 57 of blood capillary 8 is not limited to one.In addition, each when changing probe 23 three-D profile 57 be different, in addition, also there is following situation: posture such as to change at the reason due to the process along with the set-up time, and three-D profile 57 is different.
CARS resolution unit 53 plays function as with lower unit: this unit obtains the spectrophotometric spectra of at least one composition from the first observation station 5a and/or the observation station around it, and exports the first information 58 of the state of the inside representing organism 7 according to the intensity of this spectrophotometric spectra.And, CARS resolution unit 53 plays function as with lower unit: this unit the first observation station 5a and/or obtain around it different multiple parts of the degree of depth from organism surface 2, the spectrophotometric spectra of the first composition, intensity according to the spectrophotometric spectra of the first composition verifies the first observation station 5a, if necessary, also limit further or upgrade the first observation station 5a.
Biont information generation unit 56 generation comprises the Biont information 59 of the information 58 obtained from CARS resolution unit 53 and exports.
The CARS resolution unit 53 of this example possesses the function as SORS, a side in stokes light 31 and pump light 32, such as stokes light 31 are exposed to the some observation stations in the first observation station 5a, by being controlled to be irradiated with different angles relative to stokes light 31 by pump light 32 for arbitrary angle by the DM of output unit 23a.Obtained the scattered light 28 of this laser in the observation station 5 that offset by from the position of laser incidence by the excellent input block 23b of regioselectivity (resolution).Thus, according to the structure of positions different on depth direction, CARS spectrum can be obtained.
When laser machine 30 is confocal Raman spectrometer, the focal position of laser can be changed along depth direction.Therefore, it is possible to obtain organism inside, i.e. hypodermic 3D Raman spectrum from organism surface (skin surface) 2.
If comprise the Raman spectrum of the blood flowed in blood vessel in Raman spectrums different in the depth direction, then can verify the 3D profile 57 obtained in advance.By the Raman spectrum composition (spectrum peak) of the composition that selection blood middle concentration is the highest or blood middle concentration is minimum, the Raman spectrum of blood can be determined whether.Such as, relative to glucose for subcutaneous tissue, intradermal concentration, glucose concentration is in the blood vessel the highest, by resolving CARS spectrum or 3D Raman spectrum according to concentration of glucose, can judge vessel position.Also can replace paying close attention to glucose or except paying close attention to glucose, also paying close attention to the Raman spectrum comprising the composition mainly contained in the blood vessel such as hematocrit, albumin of hemocyte (leukocyte, erythrocyte), judge vessel position.
If vessel position (vessel depth) can be judged, then the Raman spectrum of this position reflects blood constituent, can from the Raman spectrum distinguishing position in real time or the minimum information (blood constituent information, organism internal information, the first information) obtaining the blood constituents such as other constituent concentration, such as the saccharifying red blood cell concentration comprised blood with sampling time for interval continuously.The monitor (sensor platform) 10 being installed on organism surface relative to the distance (degree of depth) of blood capillary 8 and position (angle) according to the posture of human body, motion and changing.Therefore, the process detecting vessel position is preferably repeatedly carried out termly.
In Fig. 4, the Raman spectrum (dotted line) of glucose and the Raman spectrum (solid line) obtained based on Sanguis Bovis seu Bubali are compared and illustrate.The Raman shift of glucose appears at 400cm
-1, 1100cm
-1front and back, also can observe in bovine blood.Thus, the known Raman spectrum that can utilize is to measure the concentration of glucose in blood.In addition, the spectrum shown in Fig. 4 is spontaneous Raman scattering.
When probe 23 being installed on organism surface (skin) 2, preferably as far as possible observation window 21 being seamlessly close to the skin 2 as organism surface, and making to there is not moisture between observation window 21 and skin 2 as far as possible.Even if there is gap, moisture, also can be measured by method such as adjustment laser power etc., but, in order to obtaining information accurately, expect there is not gap, moisture as far as possible.
In this example, probe 23 is made to be close to skin 2 via diffusibility multiple aperture plasma membrane 45.The existence of the moisture (antiperspirant) produced with dermal respiration becomes the obstacle obtained when comprising the Raman spectrum of the information of organism inside, but, by arranging diffusibility multiple aperture plasma membrane (through film) 45 between probe 23 and skin 2, can constantly moisture be discharged to the outside.Diffusibility multiple aperture plasma membrane 45 make laser 31 and 32, scattered light 28 through, affect above-mentioned observation hardly.In addition, because diffusibility multiple aperture plasma membrane 45 has elasticity, therefore, even if people's motion, also can suppress to produce gap between diffusibility multiple aperture plasma membrane 45 and skin 2.Diffusibility multiple aperture plasma membrane 45 can be pasted on probe side, also can be pasted on skin side.One example of diffusibility multiple aperture plasma membrane 45 is PDMS (polydimethylsiloxane), hybrid silica etc.
PDMS is that distance between macromolecular chain is large and represent the one of the macromolecule member material of high gas transmission coefficient.Thus, report draws, PDMS as fine bore porous membrane and play function, and have hydrophobicity, high to the affinity of organic liquid, selective penetrated property is excellent.The average fine pore of hybrid silica is 0.1nm to 0.6nm, be the micropore matter organic and inorganic hybrid films based on the silicon dioxide at least below 200 DEG C in medium with hydrothermal stability, the sol-gel processing of short chain cross-linking silane can be used manufacture.Report draws, hybrid silica is suitable for divided gas flow and Separation of Water and other micromolecular compound from the multiple organic compound such as low molecular weight alcohol.Further, relative to PDMS, thermostability is high, is suitable for the purposes under high temperature, such as has both the concentrated purposes carried out at low temperatures accumulating and at high temperature carry out discharging.Diffusibility multiple aperture plasma membrane 45 is not limited thereto.In addition, also can replace diffusibility multiple aperture plasma membrane 45 and accompany the semifluids such as the gel possessing identical function.
Also can be, as in the monitor 10 of sensor platform, be also equipped with except being equipped with Raman spectrum sensor 11 or replace being equipped with Raman spectrum sensor 11 and being equipped with ion mobility (IMS), the quality analysis sensor (MS) analyzed the composition of dermal respiration.In addition, if the sensor platform of decentralized 10, then can by the ion mobility of breath analysis, quality analysis sensor configuration near nostril or in nostril.Can wirelessly or wired mode collect information from the multiple sensors be distributed.
Return Fig. 1, the organism internal information obtained by monitor (sensor platform) 10 and the organism external information obtained by event tracking unit 140 are resolved by analytical engine 120 in the lump, by drug de-livery unit 130, organism (human body) are injected in biological active substances.
Expect that drug de-livery unit (dispensing unit) 130 realizes automatization, there is Noninvasive, possess multiple infusion of medicine path (passage), and can install or be pasted on organism (human body) 7 simply.As an example, enumerate insulin pump or the ejector of the non-invasive type using the ultrasound wave of MEMS, field-effect transistor, use nanojet.An example for the prescription drugs 152 of diabetics be basal insulin (basalinsulin) and meal time insulin (bolusinsulin).
Drug de-livery unit 130 also can be installed on human body surface with monitor 10 abreast.The biological active substances that drug de-livery unit 130 injects to human body is likely being absorbed by the body according to plan or was having an impact to the organism internal information obtained by monitor 10 before people is bulk diffusion.In this case, expect drug de-livery unit 130 to be installed on leave from monitor 10 position, such as human body contrary side.Information path between drug de-livery unit 130, analytical engine 120 and monitor 10 can be wireline pathway also can be wireless path, and they can directly connect mutually, or indirectly can connect via computer network.
There is provided the event tracking unit 140 of organism external information both can be installed on human body to analytical engine 120, also can observe the action of human body from the external world, both can be included in the server of the schedule of managing patient, also they can be combined.Typical event tracking unit 140 is sensor or the sensor group that can be installed on health.Event tracking unit 140 comprises following functions: the content of judge whether patient has a meal according to the information obtained from imageing sensor etc., having a meal, and judges that the action of patient starts motion, carries out common work, sleeps or have a rest the action case of patient as judged according to the information obtained from acceleration transducer etc.
Event tracking unit 140 also can possess the sensor of body temperature for obtaining patient, the humidity of skin surface, the outside gas epidemic disaster, air quantity, wind direction, air pressure etc. of patient.Preferred event tracking unit 140 also possesses following functions (learning functionality): the action that can learn the past of patient, and the action case of the patient of prediction after following such as one hour a period of time, after 30 minutes, after a few minutes is as having a meal, moving (training), routine work, sleep, rest.
Analytical engine 120 possesses the function of the control unit as this system 1.Analytical engine 120 also comprise according to the organism external information obtained from event tracking cell 140 predict from now on patient self or the dynamic event of surroundings thereof function (event prediction function), consider the function (inactive event analytical capabilities) that common (daily, static) event occurs and event recognition module 60.
Analytical engine 120 also comprises following functions (for dose assessment function): except considering the inside of human body information that obtains from sensor platform 10, also consider to comprise the human external information of predicted event, decides and the kind controlled from hormone, prescription drugs, mineral, nutrients etc. such as the biological active substances such as insulins of drug de-livery unit 130 injection and amount.For the decision kind of biological active substances and the function of amount, analytical engine 120 also comprises from the database acquisition content of prescription, the function (body parameter function for monitoring) of the body parameter such as size characteristic, case history of health and the function (calibration function) of correction.
Determine that comprising for dose assessment function of the kind of biological active substances of injecting to human body or throwing in and amount is decided the closed loop function of kind and amount according to organism internal information and implement to the output of closed loop function the open loop function revised according to the forecast function comprising organism external information.
The summary of the module of event recognition shown in Fig. 5 60.This event recognition module 60 can be possessed by analytical engine 120, also can be possessed by event tracking unit 140.Event recognition module 60 processes the event recognition 63 generated for controlling for medicine (drug conveying) unit 130 by the information of event prediction information 62 to the real-time GCM obtained from monitor 10 (ContinuousGlucoseMonitoring: Dynamic Blood Glucose Monitoring) 61.According to having a meal of being obtained by event tracking unit 140 and obtain the information 65 of food, motion or the information 66 of daily life (routine work), the information 67 etc. of sleep generates event information of forecasting 62.
The application program that analytical engine 120 also possesses according to using Online Store 154 etc. to provide by third party decides the kind of biological active substances and the function 68 of amount.The example of the application program provided by Online Store 154 is diabetics program, fat-reducing management program, cardiac disorder program, pressure monitoring program, life style management program, preventive assessment program, applicable program for diagnosis.As can being judged by sensor platform 10 and utilizing biological active substances to carry out the illness of object or the emergent management for the treatment of, myocardial infarction, cerebral infarction, hepatic insufficiency, renal dysfunction, hyperlipemia etc. can be enumerated.
Analytical engine 120 also comprises the function 69 exchanging information with cloud service 156.Cloud service 156 comprises doctor or nurse and family members etc. carry out the service of in-service monitoring to patient, also comprises in-service monitoring, rewriting event decides for the service of the type of medicine, amount, the function generating event database, long-range supervision service.
About analytical engine 120, the computer resource comprising CPU and memorizer also can be used to realize, and can also be LSI or ASIC, and, the chip of circuit of can recombinating also can be used to realize.
The example of the change of the glucose in blood has been shown in Fig. 6.Solid line represents by checking someway etc. glucose in blood and throwing in the situation of insulin.When measuring the concentration of glucose in blood at the sensor by penetration type, there is the delay (sensor is delayed) measured.Therefore, likely glucose amount 76 is caused to become hyperglycemia state 78 or become glycopenia state 79 because the input 77 of insulin amount that is excessively slow, too early, insulin is too much, very few.In the worst case, irreclaimable injury may be caused to human body, even may cause death.In order to avoid there is such situation, diabetics needs to prevent blood glucose value in advance and holds labile situation, and need such as to avoid fierce motion, have meal termly in the calorie ground of only taking in ormal weight etc. has the life of various restriction.
To this, in health management system arranged 1 of this example, measured continuously and in real time the glucose in blood by monitor 10.Thus, the injected volume of insulin can be controlled continuously subtly for measured concentration of glucose.Further, the generation of event (activity of patient) that event recognition module 60 detects motion, to have a meal and so on, and use the output of daily schedule, various sensor to predict the activity of patient.Analytical engine 120 determines kind and the amount of the insulin that will throw in the mode can tackling predicted state.Therefore, it is possible to the concentration of glucose in blood is controlled in the small size scope 75 little to health effect.Therefore, even diabetics also can move, have a meal in the same manner as Healthy People.
Show the main actions of health management system arranged 1 with flow chart in Fig. 7.In step 81, the observation window 21 of the probe 23 of monitor 1 is installed on the surface of skin 2 via PDMS45.In step 82, the moisture of Raman spectrum to the skin 2 of the viewing area 3 seen by observation window 21 is utilized to measure.Such as, skin surface and inner water quantities can be measured by confocal method, the distance till skin can also be measured to.In a step 83, the output of the laser used in adjusting afterwards mensuration according to the water quantities of skin surface and the distance to skin surface.When the surface of skin 2 washiness or when there is gap between skin 2 and observation window 21, the penetration power of laser changes, therefore expect adjustment laser output.Also the water quantities on the surface of skin 2 can be obtained by measuring conductivity (conductivity).
In step 84, use laser-Doppler resolution unit 51, utilize laser Doppler method to judge observation station 5a blood flow being detected in the observation station 5 in viewing area 3.By limiting the observation station 5 blood flow being detected, the position of the blood capillary 8 in viewing area 3 can be determined, can identify and be positioned at observation station 5a directly over blood capillary 8 or neighbouring.Such as, to the pumping laser 32 that viewing area 3 WBR wavelength is about 800nm, obtain the spectrum (Rayleigh scattering) of the diffused light 28 obtained from each observation station 5, if see by the expansion of the frequency of the Doppler displacement of the light of erythrocyte scattering in this spectrum, then can judge the presence or absence of blood flow.Use DM module 23a to each observation station 5 irradiating laser 32 individually.
In step 85, limit observation station (the first observation station) 5a after this becoming measuring object, locking determination object.In step 86,3D contourograph 54, based on the data of the Doppler displacement obtained at locked observation station 5a place, generates the depth profile of the blood capillary 8 of the below of the observation station 5a representing locked according to mathematical model.
Then, in step 87, contourograph 54 also uses SORS resolution unit 52 to verify the profile of the depth direction of observation station 5a further.In spatial deviation Raman spectroscopy (SORS), to observation station 5a irradiating laser, and observation station 5 place away from observation station 5a around observation station 5a obtains scattered light 28, obtains the Raman spectrum of the deep tissue of the below from skin 2 thus.The Raman spectrum that the irradiating angle that also can adjust laser generates to the profile obtaining depth direction.
In step 88, when acquisition also comprises the 3D profile 57 of the depth profile of locked observation station 5a, contourograph 54 determines the position that may there is the depth direction of the determination object (target part) of blood capillary 8.Thus, the three-dimensional position of target part is determined.
In step 89, CARS resolution unit 53 is come to obtain CARS spectrum from the position of determination object by coherent anti-Stokes Raman spectroscopy (CARS).Variable-length laser as stokes light 31 and/or pump light 32, is exposed to the observation station 5 of locked observation station 5a or its periphery with the way selection carrying out intersecting in the set degree of depth by CARS resolution unit 53.Thereby, it is possible to obtain from the composition being present in the set degree of depth from locked observation station 5a and be the anti-Stokes Raman scattered light 28 of the composition meeting the wavelength condition set according to stokes light 31 and pump light 32.Therefore, detector 40 can detect the CARS spectrum of the tissue from the position under the skin that may there is blood capillary 8.Thus, the information of blood capillary 8 can not be caused due to the Raman spectrum from other tissue to reduce, be averaged, thus the information of low noise can be obtained.
In order to the scattered light 28 from each observation station 5a is supplied to detector 40, expect to use the input block 23b possessing the combination that can form many optical fiber of multiple focus and the chopper of DM or MEMS type, stop the scattered light 28 from other observation station 5.
Further, be variable by stokes light 31 and pump light 32 are set to length, and irradiation position is limited to locked observation station 5a or its around, detector 40 side does not need to have the resolution on position and wavelength selectivity thus.Therefore, it is possible to adopt the photoelectric detector that response speed is fast, precision is high.Therefore, it is possible to supply stokes light 31 and pump light 32 by the pulsed light of short time, such as, can be supplied by the pulsed light in units of psec or femtosecond.
Thus, skin 2 can be prevented in advance by damage from laser, suppress the impact on human body, and the information from blood capillary 8 can be obtained for a long time constantly.In addition, by clamping the multiple aperture plasma membranes such as PDMS45 between skin 2, the impact of laser on skin 2 can be alleviated further.
In step 90, the information of glucose, Hb H bA1c etc. extracts and is supplied to Biont information generation unit 56 as the first information 58 by CARS resolution unit 53 from CARS spectrum.The first information 56 in blood is supplied to analytical engine 120 by Biont information generation unit 59, if needed, also will gather and makes a living interior of articles information 59 and be supplied to analytical tool 120 being generated the information collected in the process of 3D profile by contourograph 54.
In step 91, CARS resolution unit 53 obtains the change in depth making to be set to determination object (target part) and the CARS spectrum obtained with fixed interval.Based on the concentration of glucose comprised in the Raman spectrum changed along depth direction (vertical direction), for the spectrum judging the part that the spectrum of the degree of depth of target part is different relative to the degree of depth, whether be suitable as the spectrum of blood vessel.Thereby, it is possible to verify depth profile 57 all the time.In step 92, for blood vessel, in unaccommodated situation, return step 84 in the information obtained from target part, upgrade or again generate 3D profile 57.
For verifying that the Raman spectrum composition of depth profile 57 is not limited to glucose, also can be that the concentration comparatively around such as hematocrit, albumin is in the blood vessel with the composition that higher concentration exists.
Also can be set to, CARS resolution unit 53, when changing depth direction and obtaining CARS spectrum, changes the angle of stokes light 31 or pump light 32, is obtaining CARS spectrum from the position after observation station 5a displacement (skew) of regulation.By obtaining the CARS spectrum (SOCARS spectrum) after spatial deviation, the precision of the profile of depth direction can be improved further.
Also can replace CARS and obtain spectrum by resonance Raman spectroscopy, or obtain spectrum by CARS and resonance Raman spectroscopy.Also can by the Raman spectrum of incompatible for the data set of multiple Raman spectrum sensor 11 acquisition 3D.
In step 90, analytical engine 120 is not limited to obtain the organism internal information comprising glucose, can also obtain the blood constituent of cell, the albumin etc. such as chemical composition, the erythrocyte protein beyond the glucose that exists in the blood comprising and flow in blood vessel etc. and comprise the organism internal information of whole compositions that can estimate according to Raman spectrum.
In step 93, analytical engine 120 also obtains organism external information from event tracking cell 140, in step 94, judges supplying type and the amount of the biological active substances supplied in prescription unit 130 according to organism internal information and organism external information.Then, in step 95, throw in biological active substances, the such as insulin of regulation according to the analysis result of analytical engine 120 for prescription unit 130.
As discussed above, health management system arranged 1 is continuous print closed loop and the invasive healthy life parametric controller of right and wrong, the wavelength comprising Noninvasive is programmable light-dividing device, and, the activity of health is with event tracking unit, control unit and become to be integrated for prescription unit (drug de-livery unit), automatically can carry out the automatic adjustment of mensuration part.The optical quality analytical technology of Noninvasive is used in the mensuration of carrying out based on blood.Monitor 10 as sensor platform is the Optical devices based on MEMS with tunable laser, uses in the contact portion with human body the membrane tissue (thin film) that permeability is high.
In addition, this system 1 uses as platform, has and downloads and use new method (Therapeutic Method), the autgmentability of processing method.
Claims (14)
1. a monitor, from organism surface in the face of the state of organism inside monitors to have:
Probe, it comprises the observation window being installed in above-mentioned organism surface;
Illumination unit, it is to the irradiating laser at least partially of the viewing area of the above-mentioned organism surface of accessing via above-mentioned observation window;
Detecting unit, its each observation station from the multiple observation stations formed intermittently in the mode being scattered in above-mentioned viewing area two-dimensionally or formed continuously in the mode scanned above-mentioned viewing area detects the scattered light produced because laser irradiates;
From above-mentioned multiple observation station, the unit being judged as the first observation station of the scattered light of the information that can obtain the target part comprising above-mentioned organism inside is limited according to the scattered light obtained from above-mentioned multiple observation station; And
Obtain the spectrophotometric spectra of at least one composition from above-mentioned first observation station or the observation station around it and export the unit of the first information of the state representing above-mentioned organism inside according to the intensity of this spectrophotometric spectra.
2. monitor according to claim 1, is characterized in that,
Also there is following updating block, this updating block above-mentioned first observation station or obtain around it different multiple parts of the degree of depth from above-mentioned organism surface, the spectrophotometric spectra of the first composition, and limit further according to the intensity of the spectrophotometric spectra of above-mentioned first composition or upgrade above-mentioned first observation station.
3. monitor according to claim 1 and 2, is characterized in that,
Above-mentioned probe also comprises output unit, and laser is optionally guided to each point of above-mentioned multiple point by this output unit from above-mentioned illumination unit.
4. the monitor according to any one in claims 1 to 3, is characterized in that,
Above-mentioned probe also comprises input block, and scattered light is guided to above-mentioned detecting unit from each observation station of above-mentioned multiple observation station by this input block.
5. the monitor according to any one in Claims 1-4, is characterized in that,
Above-mentioned multiple observation station is set in above-mentioned viewing area with the interval of 1 μm ~ 1000 μm.
6. the monitor according to any one in Claims 1-4, is characterized in that,
Above-mentioned multiple observation station is set in above-mentioned viewing area with the interval of 10 μm ~ 100 μm.
7. the monitor according to any one in claim 1 to 6, is characterized in that,
Above-mentioned observation window is close to above-mentioned organism surface via diffusibility multiple aperture plasma membrane by above-mentioned probe.
8. a system, has:
Monitor according to any one in claim 1 to 7; And
Dispensing unit, it provides biological active substances according to the above-mentioned first information to organism.
9. system according to claim 8, is characterized in that, also has:
Action monitor unit, it obtains or predicts the external status of organism; And
Except controlling the amount of biological active substances that provides to organism from above-mentioned dispensing unit or the unit of kind according to except the above-mentioned first information, also according to the information from above-mentioned action monitor unit.
10. system according to claim 8 or claim 9, is characterized in that,
Also have and the running-active status of the above-mentioned first information and above-mentioned dispensing unit is outputted to outside unit.
The control method of 11. 1 kinds of systems, this system has from organism surface in the face of the state of organism inside carries out the monitor that monitors, in the control method of this system,
Above-mentioned monitor has:
Probe, it comprises the observation window being installed in above-mentioned organism surface;
Illumination unit, it is to the irradiating laser at least partially of the viewing area of the above-mentioned organism surface of accessing via above-mentioned observation window; And
Detecting unit, its each observation station from the multiple observation stations formed intermittently in the mode being scattered in above-mentioned viewing area two-dimensionally or formed continuously in the mode scanned above-mentioned viewing area detects the scattered light produced because laser irradiates,
This control method comprises the following steps:
According to the scattered light obtained from above-mentioned multiple observation station, from above-mentioned multiple observation station, limit the first observation station being judged as the scattered light of the information that can obtain the target part comprising above-mentioned organism inside; And
Obtain the spectrophotometric spectra of at least one composition from above-mentioned first observation station or the observation station around it, and export the first information of the state representing above-mentioned organism inside according to the intensity of this spectrophotometric spectra.
12. methods according to claim 11, is characterized in that,
Further comprising the steps of: above-mentioned first observation station or obtain around it different multiple parts of the degree of depth from above-mentioned organism surface, the spectrophotometric spectra of the first composition, and limit further according to the intensity of the spectrophotometric spectra of above-mentioned first composition or upgrade above-mentioned first observation station.
13. methods according to claim 11 or 12, is characterized in that,
Said system also has the dispensing unit providing biological active substances to organism,
The method also comprises following selection step: select by the biological active substances of above-mentioned dispensing unit dispensing and amount according to the above-mentioned first information.
14. methods according to claim 13, is characterized in that,
Said system also has the action monitor unit of the external status obtaining or predict organism,
Above-mentioned selection step comprises the following steps: except selecting by the amount of the biological active substances of above-mentioned dispensing unit dispensing or kind according to the information of said external state according to except the above-mentioned first information, also.
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| CN201811089231.9A CN109171761A (en) | 2013-05-02 | 2014-05-02 | The monitor and system monitored to organism |
| CN201811089193.7A CN109171760B (en) | 2013-05-02 | 2014-05-02 | Monitor and system for monitoring living body |
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| US20160157757A1 (en) | 2016-06-09 |
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